Ganciclovir is chemically, 9-(1,3-dihydroxy-2-propoxymethyl) guanine and has the structural formula I: It is one of the most important acyclic nucleosides having significant antiviral properties, especially effective against members of the herpes family and a few other DNA viruses.
The simplest synthetic approach to the N-9 substituted guanine compounds involves the direct alkylation of appropriately substituted 2-aminopurines e.g. guanine derivatives. However, the major drawback in this process is that it always results in a mixture of N-9 and N-7 alkylation products. Since alkylation of guanine derivatives like diacetyl/monoacetyl guanine is a thermodynamically controlled reaction, N-7 isomer is always formed. However, the N-9 isomer being thermodynamically more stable is produced as the major product. The unwanted N-7 isomer is difficult to separate from the desired N-9 isomer and is generally purified by costly and tedious processes requiring chromatographic separation and are highly undesirable on a commercial scale.
Some of the prior art processes for the manufacture of aciclovir/ganciclovir are disclosed in BE 833006; U.S. Pat. Nos. 4,199,574 and 4,355,032; Chem Pharm Bull, 36 (3) 1153-1157 and JP 63-107982 and 59-80685, and EP 532878. One such U.S. Pat. No. 5,821,367 describes a regiospecific process which comprises reacting protected guanine derivative with an alkylating agent selected from 2-oxa-1,4-butanediol diacetate, 1-4-diacetoxy-3-acetoxymethyl-2-oxa-butane, and 1,4-dibenzyloxy-3-acetoxymethyl-2-oxabutane in the absence of solvent or any acid catalyst to obtain the penultimate intermediates which are then converted to acylic nucleosides (acyclovir and ganciclovir). U.S. Pat. No. 6,043,364 teaches a process for the conversion of N-7 isomer to N-9 isomer by heating a suspension of the N-7 isomer in an alkylating agent.
However, the separation of N-9 isomer from the form N-7 isomer in said patent has been achieved by column chromatography only. Therefore, the process does not offer any additional benefits from commercial point of view.
Accordingly, none of the processes heretofore described are completely satisfactory.